Bicyclic heteroaryl derivatives as CFTR potentiators
The present invention relates to 5,7-disubstituted-imidazo[5,1-f][1,2,4]triazine-4-amine derivatives, and pharmaceutically acceptable salts thereof. The compounds are potentiators of Cystic Fibrosis Transmembrane conductance Regulator (CFTR). The invention also discloses pharmaceutical compositions comprising the compounds, optionally in combination with additional therapeutic agents, and methods of potentiating, in mammals, including humans, CFTR by administration of the compounds. These compounds are useful for the treatment of cystic fibrosis (CF), asthma, bronchiectasis, chronic obstructive pulmonary disease (COPD), constipation, Diabetes mellitus, dry eye disease, pancreatitis, rhinosinusitis, Sjögren's Syndrome, and other CFTR associated disorders.
1. A compound of Formula IB:
wherein Hal is selected from the group consisting of chloro, bromo, and iodo;
Y is a five membered heteroaryl comprising one to four heteroatoms each of which is independently selected from the group consisting of N, O and S(O) n ; wherein the heteroaryl is optionally substituted with one to three substituents each of which is independently selected from the group consisting of halo, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl;
Z is phenyl, optionally substituted with one to three halo;
R 1a and R 1b are each independently selected from the group consisting of H, OH, halo, C 1 -C 6 alkyl optionally substituted with one to three substituents each of which is independently selected from the group consisting of halo, —OH, C 1 -C 3 alkoxy, C 3 -C 7 cycloalkyl and a four to seven membered heterocycloalkyl comprising one to three heteroatoms each of which is independently selected from the group consisting of N, O and S(O) n , C 3 -C 7 cycloalkyl optionally substituted with one to three substituents each of which is independently selected from the group consisting of —OH, halo and C 1 -C 6 alkyl, and four to seven membered heterocycloalkyl comprising one to three heteroatoms each of which is independently selected from the group consisting of N, O and S(O) n ; and wherein the four to seven membered heterocycloalkyl is optionally substituted with one to three substituents each of which is independently selected from the group consisting of —OH, halo and C 1 -C 6 alkyl; or
R 1a and R 1b taken together with the carbon to which they are attached form a C 3 -C 7 cycloalkyl or a four to seven membered heterocycloalkyl comprising one to three heteroatoms each of which is independently selected from the group consisting of N, O and S(O) n ; and wherein the C 3 -C 7 cycloalkyl or four to seven membered heterocycloalkyl are optionally substituted with one to three substituents each of which is independently selected from the group consisting of —OH, halo and C 1 -C 6 alkyl; and
wherein n at each occurrence is independently 0, 1 or 2.